Etiology and Outcomes of Patients with Extreme Hyperbilirubinemia in Korea: A Retrospective Cohort Study.

Background/Aim: Extreme hyperbilirubinemia is occasionally observed in intensive care unit (ICU) and non-ICU settings. This study examined the etiologies of extreme hyperbilirubinemia (bilirubin level ≥12 mg/dL) and the factors associated with the 30-day mortality. Methods: This retrospective observational cohort study identified 439 patients with extreme hyperbilirubinemia at the Gyeongsang National University Changwon Hospital between 2016 and 2020. The patients were classified into three groups and 11 diseases according to their etiology. The risk factors associated with 30-day mortality at the baseline were investigated using the Cox proportional hazards model. Results: Of 439 patients with extreme hyperbilirubinemia, 287, 78, and 74 were in the liver cirrhosis/malignancy group, the ischemic injury group, and the benign hepatobiliary-pancreatic etiological group, respectively, with corresponding 30-day mortality rates of 42.9%, 76.9%, and 17.6%. The most common disease leading to hyperbilirubinemia was a pancreatobiliary malignancy (28.7%), followed by liver cirrhosis (17.3%), hepatocellular carcinoma (10.9%), and liver metastases (8.4%). The etiologies of hyperbilirubinemia, obstructive jaundice, infection, albumin level, creatinine level, and prothrombin time-international normalized ratio were independently associated with the 30-day mortality. Conclusions: This study suggests three etiologies of extreme hyperbilirubinemia in the ICU and non-ICU settings. The prognosis of patients with extreme hyperbilirubinemia depends largely on the etiology and the presence of obstructive jaundice.

Multiorgan Dysfunction in a Patient With Adult-Onset Still's Disease Flare: A Case Report.

Adult-onset Still's disease (AOSD) is a rare multisystem inflammatory disorder. A 71-year-old lady who was on treatment for AOSD presented with clinical evidence of heart failure and was subsequently found to have impaired renal and hepatic function. Following extensive workup including a liver biopsy, the cause of liver dysfunction was determined to be congestive hepatopathy, while renal dysfunction was presumed to stem from the low output state. The etiology of myocardial dysfunction, driving liver and kidney injury, was considered to be myocarditis from AOSD or global myocardial dysfunction from a systemic inflammatory state. Management involved pulse-dose glucocorticoids followed by taper and anakinra for AOSD, alongside goal-directed medical therapy for cardiac failure. At follow-up after a month, hepatic and renal function had fully recovered, whereas cardiac function remained compromised, evidenced by persistently depressed ejection fraction and global hypokinesia on a repeat echocardiogram. This report delineates a systematic approach to multiorgan dysfunction in a patient with a rare condition such as AOSD and reviews the reported causes of hepatic and cardiac involvement in AOSD.

Ischemic Hepatitis and Septic Shock Secondary to Murine Typhus Infection in Pregnancy.

Infection with murine typhus may be associated with significant morbidity. With nonspecific symptoms and laboratory abnormalities, diagnosis may be challenging. In this case, a pregnant patient presented with complaints of fevers and myalgias. Her laboratory results included severe transaminitis as well as thrombocytopenia and hyponatremia. She ultimately required vasopressor support and intensive care unit admission despite fluid resuscitation and broad-spectrum antibiotics. Empiric doxycycline was initiated due to suspicion for murine typhus, which laboratory testing later confirmed. Her clinical status improved with these interventions. This was a severe case of murine typhus resulting in septic shock and ischemic hepatitis. It is important to know the typical findings of murine typhus and consider it in a differential diagnosis, especially when practicing in endemic areas.

Severe Hepatitis Complicating Olmesartan Enteropathy: A Case Report.

Introduction: Olmesartan, an angiotensin II receptor antagonist, is associated with an uncommon complication of enteropathy that presents insidiously, usually months to years after initial commencement of anti-hypertensive therapy which can be dose-dependent. It has a variable spectrum of clinical presentation but commonly presents as a moderate to severe malabsorptive process with potential severe complications related to poor end-organ perfusion. Lymphocytic gastritis and microscopic colitis are often noted in patients presenting with olmesartan-induced enteropathy; however, hepatic involvement has been less frequently observed. Case Presentation: We illustrate a case of a 43-year-old female presenting with 2 weeks of profuse non-bloody diarrhea in the context of olmesartan enteropathy which was complicated by an acute severe ischemic and enteropathic hepatopathy. Conclusion: Our case prompts clinicians to maintain a high index of suspicion in cases presenting with a seronegative enteropathy and concurrent acute liver injury while on olmesartan therapy. Cessation of olmesartan therapy resulted in prompt resolution of diarrheal symptoms and normalization of the acute transaminitis on subsequent three-week follow-up.

Ischemic hepatitis due to an occlusion of visceral arteries: a case report.

Ischemic hepatitis due to mesenteric artery occlusion is extremely rare. This is due to the function of the collateral network of the celiac-mesenteric arterial system and portal venous flow. A 64-year-old male presented with abdominal pain, a significantly reduced general condition, a weight loss of 20 kg in 4 months. Computed tomography showed occlusion of the celiac trunk and the superior mesenteric artery and hypodense lesions in the liver. We performed an antegrade visceral reconstruction with a bifurcated 12-6 mm Dacron graft from the supra-celiac aortic donor to the superior mesenteric and celiac arteries. The postoperative course and follow-up were uneventful.

A Case of Cocaine-Induced Acute Liver Failure Reversed With N-Acetylcysteine.

Acute liver failure (ALF) is a life-threatening injury that is most often caused by drug-induced injury, including acetaminophen overdose, in the United States. The hallmarks of ALF are hepatic encephalopathy and coagulopathy in a patient without an established history of liver disease. While acetaminophen overdose has an antidote, that is N-acetylcysteine (NAC), when given acutely, most other causes of hepatic failure require an urgent liver transplant. In this paper, we report a case of cocaine-induced acute liver failure that was reversed with the administration of NAC. Our case began when a middle-aged male presented to the emergency department complaining of nausea, vomiting, fatigue, and confusion for the past three days. His past medical history was pertinent for a history of opioid use disorder and his physical exam was remarkable for somnolence, asterixis, and periumbilical ecchymoses. His initial lab results showed markedly elevated liver function tests, prolonged coagulation studies, and a urine drug screen that was positive for cocaine. During the patient's interview, his vital signs became unstable. He was intubated for airway protection and transferred to a tertiary care facility for liver transplant evaluation with the diagnosis of cocaine-induced acute liver failure. There he received NAC, lactulose, rifaximin, and vasopressors. On day two of treatment, his clinical condition greatly improved, and he was extubated. He continued to receive NAC until day five when his liver function tests and coagulopathy improved enough to stop treatment. This case report highlights the clinical benefit of NAC in a case of cocaine-induced acute liver failure, improving the patient's survival and eliminating his need for a liver transplant.

Clinical course of congestive hepatopathy pre/post heart transplantation.

BACKGROUND AND AIMS: Heart failure (HF) might lead to increased hepatic venous pressure, thereby impairing hepatic blood outflow and subsequently inducing congestive hepatopathy. We aimed to evaluate prevalence of congestive hepatopathy in patients undergoing heart transplantation (HTX) as well as their post-transplant course. METHODS: Patients undergoing HTX from 2015-2020 at the Vienna General Hospital were included (n = 205). Congestive hepatopathy was defined by hepatic congestion on abdominal imaging and hepatic injury. Laboratory parameters, ascites severity, and clinical events were assessed and post-HTX outcomes evaluated. RESULTS: At listing, 104 (54%) patients showed hepatic congestion, 97 (47%) hepatic injury, and 50 (26%) had ascites. Congestive hepatopathy was diagnosed in 60 (29%) patients, who showed more often ascites, lower serum sodium and cholinesterase activity, and higher hepatic injury markers. Mean albumin-bilirubin (ALBI)-score as well as (modified)-model for end-stage liver disease (MELD)-scores were higher in patients with congestive hepatopathy. Median levels of laboratory parameters/scores normalised after HTX, and ascites resolved in most patients with congestive hepatopathy (n = 48/56, 86%). The post-HTX (median follow-up 55.1 months) survival was 87% and liver-related events were rare (3%). Severe ascites, low cholinesterase, and MELD/MELD-XI were associated with ascites persistence/death 1­year after HTX. Age, male sex, and severe ascites were the only independent predictors of post-HTX mortality. Both ALBI and MELD-scores were robust indicators of post-HTX survival when measured 4 weeks after HTX (ALBI log-rank test p < 0.001; MELD log-rank test p = 0.012). CONCLUSION: Congestive hepatopathy and ascites were mostly reversible after HTX. Liver-related scores and ascites improve prognostication in patients after HTX.

Retrograde open celiac stenting for ischemic hepatitis after pancreaticoduodenectomy.

A 74-year-old man with pancreatic cancer had undergone pancreaticoduodenectomy and subsequently developed ischemic hepatitis secondary to high-grade celiac artery stenosis. Celiac antegrade stenting via brachial artery access was unsuccessful, and open antegrade bypass would have required takedown of the pancreatic and/or biliary anastomoses for adequate exposure. Retrograde open celiac stenting was, therefore, successfully performed via the gastroduodenal artery stump. His ischemic hepatitis resolved, and he was ultimately discharged with dual antiplatelet therapy. Computed tomography angiography at 6 months demonstrated a widely patent celiac stent. Retrograde open celiac stenting via the gastroduodenal artery stump is an alternative to open bypass for celiac revascularization not amenable to percutaneous antegrade stenting in patients who have undergone pancreaticoduodenectomy.

Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study.

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia-reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (-14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.

Ischemic Hepatitis Induced by Uremic Cardiac Tamponade in a Patient with Underlying Hepatitis C with a Review of the Literature.

Ischemic hepatitis is a rare cause of acute liver injury (ALI) and is associated with various etiologies including cardiac failure, trauma, hemorrhage, and respiratory failure that all result in poor perfusion and oxygen delivery to the liver. A 30-year-old patient complained of orthopnea with a history of hepatitis C treatment and is currently on hemodialysis (HD) due to chronic allograft rejection. Also, he had previous pericardial effusion (PEFF) due to inadequate dialysis. Laboratory tests on admission revealed urinary tract infection, HCV PCR positive, and high blood urea nitrogen. Computed tomography of the chest showed massive PEFF. Echocardiography revealed a massive PEFF that measured 3.6 cm on the apical four-chamber window, and the inferior vena cava diameter was 27 mm with a decreased collapsibility of ˂20% in inspiration. The patient was treated for UTI and started the treatment for HCV. Also, increased HD sessions with minimal heparinization of the dialyzer circuit were obtained along with daily monitoring of PEFF by echocardiography. At first, echocardiography did not reveal frank signs of cardiac tamponade, but after 2 sessions of HD, the patient developed chest pain, worsening orthopnea, JVP elevation, and dropping of the systolic BP. Echocardiography showed specific signs of cardiac tamponade, which included an increased effusion to 4.4 cm and changes in velocities of the mitral valve and tricuspid valve during the respiratory cycle by more than 25% and 40%, respectively. The patient was transmitted to ICU, and pericardiocentesis was obtained. Two days later, asymptomatic ALI was noticed by elevation of the following tests: ALT, AST, LDH, PT, and INR. However, ALI exhibits a rapid and spontaneous resolution to nearly normal tests after 10 days. Although the patient was hemodynamically stable, the liver injury occurred and might be attributed to ESRD and hypertension that caused thickened heart walls, diastolic dysfunction, and subsequently hepatic congestion, in addition to previous liver injury due to HCV. We present a rare case of ALI caused by uremic pericardial tamponade with an overview of the current literature with regard to this entity. So, we emphasize monitoring liver function tests in the context of PEFF, especially in patients with chronic kidney disease.

Case of Ischemic Hepatitis in the Setting of HFpEF Exacerbated by Persistent Atrial Fibrillation.

Congestive hepatopathy in the setting of chronic heart failure is predominantly cholestatic. Severe hepatocellular injury can be seen in cardiogenic shock, usually in an acute setting with severe reduction in ejection fraction and with significant hypotension. Hepatic ischemia with preserved ejection fraction in the setting of atrial fibrillation has not been widely recognized, although mild elevations of liver enzymes have been seen in such patients in the chronic state. We present a patient with preserved ejection fraction, rapid atrial fibrillation with hypotension who had ischemic hepatitis, with aspartate aminotransferase and alanine aminotransferase over one thousand.

Prevalence, clinical characteristics and outcomes of hypoxic hepatitis in critically ill patients.

BACKGROUND: Hypoxic hepatitis (HH) is an important clinical entity in patients in the intensive care unit (ICU). The aims of the study were to assess the etiology, clinical characteristics and outcomes of HH in the ICU of a tertiary hospital. Secondary aim was to analyze the effects of concomitant ischemia in other organs than the liver. METHODS: All patients with HH, 2011-2018, in a university hospital ICU were included. Data were collected on etiology, relevant clinical data and outcome. HH was defined by an increase in aminotransferases ≥10 times the upper limit of normal within 48 h from a clinical event of cardiac, circulatory or respiratory failure. Other causes of liver cell necrosis were excluded. RESULTS: Of 9,931 patients hospitalized in the ICU, 159 (1.6%) fulfilled criteria for HH. In-hospital mortality occurred in 85 (53%) and 60 (38%) survived one year. Median ICU stay was five days (interquartile range (IQR) 3-10) and median hospital stay 16 days (IQR 7-32). Shock (48%), cardiac arrest (25%) and hypoxia (13%) were the most common causes of HH. Acute kidney injury (81%), rhabdomyolysis (50%), intestinal ischemia (6%) and ischemic pancreatitis (3%) occurred concomitantly. Age (odds ratio (OR) 1.05 (95% CI 1.02-1.09)), serum lactate (OR 2.61 (95% CI 1.23-5.50)) and lactate dehydrogenase (OR 1.14 (95% CI 1.02-1.27)) were predictors of mortality. CONCLUSIONS: Hypoxic hepatitis was related to shock in approximately 50% of cases and associated with high in-hospital mortality. HH was commonly associated with ischemia in other organs. In-hospital mortality was associated with age, lactate and LD.

Coronavirus Disease 2019 and Liver Injury: A Retrospective Analysis of Hospitalized Patients in New York City.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is a global threat, affecting more than 100 million people and causing over 2 million deaths. Liver laboratory test abnormalities are an extrapulmonary manifestation of COVID-19, yet characterization of hepatic injury is incomplete. Our objective was to further characterize and identify causes of liver injury in patients with COVID-19. METHODS: We conducted a retrospective cohort study of 551 patients hospitalized with COVID-19 at NewYork-Presbyterian Hospital/Columbia University Irving Medical Center between March 1, 2020 and May 31, 2020. We analyzed patient demographics, liver laboratory test results, vital signs, other relevant test results, and clinical outcomes (mortality and intensive care unit admission). RESULTS: Abnormal liver laboratory tests were common on hospital admission for COVID-19 and the incidence increased during hospitalization. Of those with elevated serum alanine aminotransferase and/or alkaline phosphatase activities on admission, 58.2% had a cholestatic injury pattern, 35.2% mixed, and 6.6% hepatocellular. Comorbid liver disease was not associated with outcome; however, abnormal direct bilirubin or albumin on admission were associated with intensive care unit stay and mortality. On average, patients who died had greater magnitudes of abnormalities in all liver laboratory tests than those who survived. Ischemic hepatitis was a mechanism of severe hepatocellular injury in some patients. CONCLUSIONS: Liver laboratory test abnormalities are common in hospitalized patients with COVID-19, and some are associated with increased odds of intensive care unit stay or death. Severe hepatocellular injury is likely attributable to secondary effects such as systemic inflammatory response syndrome, sepsis, and ischemic hepatitis.

[The pathogenesis of ischemic hepatitis].

Ischemic hepatitis is inflammation caused by necrosis of liver cells due to ischemia and hypoxia caused by low cardiac output or septic shock. It is often complicated by heart failure or severe septic shock. One of the pathogenesis of ischemic hepatitis is hepatocyte injury caused by ischemia and hypoxia, which results in damage-associated molecular patterns (DAMPs) release and binding to membrane receptors such as toll like receptors (TLRs) to cause inflammatory reactions.The other is when the ischemic liver is reperfused, hepatocyte mitochondrias will produce a large amount of ROS causing ischemia reperfusion injury. These two mechanisms and related molecular pathways are elaborated in this paper.

Acute liver failure in ruptured sinus of Valsalva aneurysm.

A sinus of Valsalva aneurysm (SOVA) is a rare cardiac defect in which the aortic root area between the aortic annulus and the sinotubular junction is dilated. We present a case of acute liver failure (ALF) in a 21-year-old man secondary to ruptured SOVA inducing severe ischemic hepatitis. The patient presented clinically with classical ALF. The liver ultrasound reported hepatomegaly with pulsatile portal flow and dilated hepatic veins. A transthoracic echocardiogram revealed focal aneurysmal dilatation of the aortic root with flow across the aneurysm toward the right atrium and elevated right chambers pressures. The surgical repair of the non-coronary SOVA was successful, and post-operatively, liver transaminases improved, and ALF resolved. Given that ruptured SOVA can be surgically repaired, hepatologists should be aware of this diagnosis in a young patient with ALF.

Epidemiology and outcomes of marked elevations of alanine aminotransferase >1000 IU/L in an Australian cohort.

BACKGROUND AND AIM: Marked elevations of alanine aminotransferase (ALT) are caused by a limited number of underlying pathologies, including hepatic ischemia, drugs/toxins, viral hepatitis, and-rarely-autoimmune hepatitis. The aim of this study was to determine the relative incidence of pathologies resulting in ALT greater than 1000 IU/L and factors predicting clinical outcomes in an Australian cohort. METHODS: A retrospective cohort study of all adult patients with ALT levels greater than 1000 IU/L between January 2013 and December 2015 was conducted at a large teaching hospital network in Australia. Multivariable logistic regression analysis was used to determine predictors of etiology and mortality. RESULTS: There were 287 patients identified with ALT levels greater than 1000 IU/L. The most common causes were ischemia (44%), drugs/toxins (19%), biliary obstruction (16%), and viral hepatitis (7%). Independent predictors of a diagnosis of ischemic hepatitis included (adjusted odds ratio; 95% confidence interval): hypotension (29.2; 8.2-104.7), chronic obstructive pulmonary disease (COPD) (20.2; 2.8-145.3), coronary artery disease (12.9; 1.7-98.9), congestive cardiac failure (7.8; 1.2-49.2), diabetes mellitus (7.4; 1.6-33.9), metabolic acidosis (6.2; 2.0-19.4), gamma-glutamyltransferase < 135 IU/L (5.1; 1.5-17.6), and albumin <34 g/L (3.4; 1.1-11.0). Independent risk factors for all-cause 28-day mortality included: septic shock (14.7; 4.3-50.7), metabolic acidosis (7.3; 2.5-21.3), history of COPD (5.4; 1.6-17.8), cardiogenic shock (4.3; 1.6-11.7), prothrombin time ≥ 20 s (3.7; 1.5-9.2), and age ≥ 65 years (3.0; 1.3-7.2). CONCLUSIONS: Ischemic hepatitis was the most common cause of ALT levels greater than 1000 IU/L and was associated with high mortality.

Relationship between Heart Disease and Liver Disease: A Two-Way Street.

In clinical practice, combined heart and liver dysfunctions coexist in the setting of the main heart and liver diseases because of complex cardiohepatic interactions. It is becoming increasingly crucial to identify these interactions between heart and liver in order to ensure an effective management of patients with heart or liver disease to provide an improvement in overall prognosis and therapy. In this review, we aim to summarize the cross-talk between heart and liver in the setting of the main pathologic conditions affecting these organs. Accordingly, we present the clinical manifestation, biochemical profiles, and histological findings of cardiogenic ischemic hepatitis and congestive hepatopathy due to acute and chronic heart failure, respectively. In addition, we discuss the main features of cardiac dysfunction in the setting of liver cirrhosis, nonalcoholic fatty liver disease, and those following liver transplantation.

Mechanisms and biomarkers of liver regeneration after drug-induced liver injury.

Liver, the major metabolic organ in the body, is known for its remarkable capacity to regenerate. Whereas partial hepatectomy (PHx) is a popular model for the study of liver regeneration, the liver also regenerates after acute injury, but less is known about the mechanisms that drive it. Recent studies have shown that liver regeneration is critical for survival in acute liver failure (ALF), which is usually due to drug-induced liver injury (DILI). It is sometimes assumed that the signaling pathways involved are similar to those that regulate regeneration after PHx, but there are likely to be critical differences. A better understanding of regeneration mechanisms after DILI and hepatotoxicity in general could lead to development of new therapies for ALF patients and new biomarkers to predict patient outcome. Here, we summarize what is known about the mechanisms of liver regeneration and repair after hepatotoxicity. We also review the literature in the emerging field of liver regeneration biomarkers.

Hypoxic liver injury after in- and out-of-hospital cardiac arrest: Risk factors and neurological outcome.

BACKGROUND: Hypoxic liver injury (HLI) is a frequent and life-threatening complication in critically ill patients that occurs in up to ten percent of critically ill patients. However, there is a lack of data on HLI following cardiac arrest and its clinical implications on outcome. Aim of this study was to investigate incidence, outcome and functional outcome of patients with HLI after in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA). METHODS: We conducted an analysis of a cardiac arrest registry data over a 7-year period. All patients with non-traumatic OHCA and IHCA with return of spontaneous circulation (ROSC) treated at the emergency department of a tertiary care hospital were included in the study. HLI was defined according to established criteria. Predictors of HLI, occurrence, clinical and neurological outcome were assessed using multivariable regression. RESULTS: Out of 1068 patients after IHCA and OHCA with ROSC, 219 (21%) patients developed HLI. Rate of HLI did not differ significantly in IHCA and OHCA patients. Multivariate regression analysis identified time-to-ROSC [OR 1.18, 95% CI (1.01-1.38); p < 0.05], presence of cardiac failure [OR 2.57, 95% CI (1.65-4.01); p < 0.001] and Charlson comorbidity index [OR 0.83, 95% CI (0.72-0.95); p < 0.01] as independent predictors for occurrence of HLI. Good functional outcome was significantly lower in patients suffering from HLI after 28-days (35% vs. 48%, p < 0.001) and 1-year (34% vs. 44%, p < 0.001). Occurrence of HLI was associated with unfavourable neurological outcome [OR 1.74, 95% CI (1.16-2.61); p < 0.01] in multivariate regression analysis. CONCLUSION: New onset of HLI is a frequent finding after IHCA and OHCA. HLI is associated with increased mortality, unfavourable neurological and overall outcome.